Abstract:

Disclosed herein are the improved processes for the preparation of
different forms of (S)-(+)-Clopidogrel besylate, pharmaceutical
compositions containing them and their use in medicine.

Claims:

1. A process for the preparation of amorphous form of (S)-(+)-Clopidogrel
besylate comprising,i. treating Clopidogrel base with benzene sulfonic
acid in suitable solvent(s) selected from tetrahydrofuran, methyl
isobutyl ketone, or their suitable mixturesii. removing the solvent to
obtain the amorphous form.

2. A process for the preparation of crystalline form of
(S)-(+)-Clopidogrel besylate comprising,i. treating Clopidogrel base with
benzene sulfonic acid in suitable solvent(s) selected from methyl
tertiary butyl ether, suitable C2-C12 alcohols which may be linear or
branched, primary, secondary or tertiary alcohols or their suitable
mixturesii. suitably removing the solvent.

3. A process for the preparation of crystalline form of
(S)-(+)-Clopidogrel besylate as claimed in claim 2, wherein optionally,
the reaction mixture is seeded with crystals of (S)-(+)-Clopidogrel
besylate.

4. A process for the preparation of crystalline form of
(S)-(+)-Clopidogrel besylate wherein the amorphous (S)-(+)-Clopidogrel
besylate as prepared in claim 1, is further converted to the crystalline
form by dissolving in suitable solvent(s), selected from methyl tertiary
butyl ether, suitable C2-C12 alcohols which may be linear or branched,
primary, secondary or tertiary alcohols or their suitable mixtures and
subsequently suitably removing the solvent.

5. A process for the preparation of crystalline form of
(S)-(+)-Clopidogrel besylate as claimed in claim 4 wherein optionally,
the reaction mixture is further seeded with crystals of
(S)-(+)-Clopidogrel besylate.

6. A pharmaceutical composition comprising the besylate salts of
Clopidogrel as claimed in claim 1 prepared according to the present
invention.

Description:

FIELD OF INVENTION

[0001]The present invention relates to an improved processes for the
preparation of different forms of (S)-(+)-Clopidogrel besylate,
pharmaceutical compositions containing them and their use in medicine.

TECHNICAL BACKGROUND

[0002]Clopidogrel has the following structure (1)

##STR00001##

[0003]It is available in the market as its bisulfate salt and is marketed
by Sanofi-Synthelabo as "Plavix" having the general formula (II)

##STR00002##

[0004]Clopidogrel is an inhibitor of platelet aggregation and is marketed
as an antianginal agent, antiplatelet agent and is found to decrease
morbid events in people with established atherosclerotic cardiovascular
disease and cerebrovascular diseases.

[0005]The therapeutic application of Clopidogrel as blood-platelet
aggregation inhibiting agents and antithrombotic agent and its
preparation is disclosed in U.S. Pat. No. 4,529,596. U.S. Pat. No.
4,847,265 describes the process for the preparation of the hydrogen
sulfate salt of Clopidogrel.

[0006]Polymorphs of Clopidogrel bisulfate has been described in U.S. Pat.
Nos. 6,504,040 and 6,429,210. We have disclosed novel polymorphs of
Clopidogrel bisulfate in our published application WO2004081016.

[0007]U.S. Pat. No. 4,847,265 discloses that the dextrorotatory enantiomer
of formula (I) of Clopidogrel has an excellent antiaggregant platelet
activity, whereas the corresponding levorotatory enantiomer of (I) is
less tolerated of the two enantiomers and is less active. U.S. Pat. No.
4,847,265 also describes various other salts of Clopidogrel base as well
as of the dextrorotatory isomer like its hydrochloride, carboxylic acid
and sulfonic acids salts were prepared. Specifically salts of acetic,
benzoic, fumaric, maleic, citric, tartaric, gentisic, methanesulfonic,
ethanesulfonic, benzenesulfonic and lauryl sulfonic acids were prepared.
However, according to the patent, these salts usually precipitated in
amorphous form and/or they were hygroscopic making them difficult to
handle in an industrial scale. Also, no process and no data corresponding
to any of these salts are reported. The specification also describes
salts of dobesilic acid (m.p.=70° C.) and para-toluenesulfonic
acid, having a melting point of 51° C., the purification of which,
as accepted in the patent, proved to be difficult.

[0008]Clopidogrel besylate which is at least partly in crystalline
(solvated) forms have been disclosed by Helm in their published
applications WO2004072084 (US20050256152, EP 1480985 B1) and
WO2004072085. Subsequently, Helm disclosed non-solvated forms in their
application no. US20050203122.

[0009]We have disclosed new polymorphic forms of Clopidogrel mesylate,
Clopidogrel besylate and Clopidogrel tosylate in our published
Application No. WO 2004106344, which are stable, free flowing, scalable,
useful industrially and have important pharmacological properties. We
herein disclose improved processes for preparing different forms of
(S)-(+) Clopidogrel besylate.

EMBODIMENT(S) OF THE PRESENT INVENTION

[0010]In an embodiment of the present invention is disclosed improved
processes for the preparation of different forms of (S)-(+) Clopidogrel
besylate.

[0011]In a further embodiment of the present invention is provided
improved processes for the preparation of crystalline (S)-(+) Clopidogrel
besylate.

[0012]In a still further embodiment is provided improved processes for the
preparation of amorphous (S)-(+) Clopidogrel besylate.

[0013]As a further embodiment of the present invention are provided
pharmaceutical compositions containing and the use of the various forms
of (S)-(+) Clopidogrel besylate prepared according to the processes
described herein.

[0017]The amorphous form described in the specification is prepared by the
process described below.

[0018]Clopidogrel base in suitable solvents is treated with benzene
sulfonic acid, the solvent is evaporated to dryness and amorphous form is
separated. Suitable solvents is selected from tetrahydrofuran (THF),
methyl isobutyl ketone and the like or mixtures thereof.

[0019]The crystalline form of (S)-(+)-Clopidogrel besylate is prepared by
any of the processes described below, or suitable combinations of one or
more of any of the processes described below: [0020]i) Clopidogrel base
in suitable solvents is treated with benzene sulfonic acid and the
solvent is removed to obtain the crystalline form. Suitable solvent(s)
may be selected from methyl tertiary butyl ether, or suitable alcohols
selected from C2-C12 alcohols which may be linear or branched,
primary, secondary or tertiary alcohols such as ethanol, propanol,
isopropanol, 1-butanol, 2-butanol, isobutanol, t-butanol, 1-pentanol,
1-hexanol, 2-hexanol, 3-hexanol, isohexanol, 1-heptanol, 2-heptanol,
3-heptanol, 4-heptanol, octanol, isooctanol, decanol, dodecanol and the
like or mixtures thereof. [0021]ii) Amorphous (S)-(+)-Clopidogrel
besylate is dissolved in suitable solvents and the solvent is removed to
obtain the crystalline form. Suitable solvent(s) may be selected from
methyl tertiary butyl ether or suitable alcohols selected from
C2-C12 alcohols which may be linear or branched, primary,
secondary or tertiary alcohols such as ethanol, propanol, isopropanol,
1-butanol, 2-butanol, isobutanol, t-butanol, 1-pentanol, 1-hexanol,
2-hexanol, 3-hexanol, isohexanol, 1-heptanol, 2-heptanol, 3-heptanol,
4-heptanol, octanol, isooctanol, decanol, dodecanol and the like or
mixtures thereof. [0022]iii) Clopidogrel base in suitable solvents is
treated with benzene sulfonic acid, the solution is seeded with crystals
of (S)-(+)-Clopidogrel besylate and the solvent is removed to obtain the
crystalline form. Suitable solvent(s) may be selected from methyl
tertiary butyl ether or suitable alcohols selected from C2-C12
alcohols which may be linear or branched, primary, secondary or tertiary
alcohols such as ethanol, propanol, isopropanol, 1-butanol, 2-butanol,
isobutanol, t-butanol, 1-pentanol, 1-hexanol, 2-hexanol, 3-hexanol,
isohexanol, 1-heptanol, 2-heptanol, 3-heptanol, 4-heptanol, octanol,
isooctanol, decanol, dodecanol and the like or mixtures thereof.
[0023]iv) Amorphous (S)-(+)-Clopidogrel besylate is dissolved in suitable
solvent(s) and the solution is seeded with crystals of
(S)-(+)-Clopidogrel besylate. The solvent is removed to obtain the
crystalline form. Suitable solvent(s) may be selected from methyl
tertiary butyl ether or suitable alcohols selected from C2-C12
alcohols which may be linear or branched, primary, secondary or tertiary
alcohols such as ethanol, propanol, isopropanol, 1-butanol, 2-butanol,
isobutanol, t-butanol, 1-pentanol, 1-hexanol, 2-hexanol, 3-hexanol,
isohexanol, 1-heptanol, 2-heptanol, 3-heptanol, 4-heptanol, octanol,
isooctanol, decanol, dodecanol and the like or mixtures thereof.

[0024]Alternatively, the processes described above can be repeated by
using the Clopidogrel base prepared according to the improved processes
described by the applicant in U.S. Pat. No. 6,635,763.

[0025]The amorphous Clopidogrel benzene sulfonate (Clopidogrel besylate)
prepared according to the process of the present invention has a melting
point in between the range of 85° C.-95° C.

[0026]The crystalline Clopidogrel benzene sulfonate (Clopidogrel besylate)
prepared according to the process of the present invention has a melting
point in between the range of 130° C.-135° C.

[0027]The following non-limiting examples illustrate the inventor's
improved processes for the preparation of different forms of (S)-(+)
Clopidogrel besylate discussed in the invention and should not be
construed to limit the scope of the invention in any way.

EXAMPLE 1

Preparation of Amorphous Clopidogrel Besylate

[0028]Clopidogrel base was dissolved in THF. To it, benzene sulfonic acid
was added at 20° C., and the reaction mixture was heated to reflux
temperature for 2 to 10 hr. The solvent was evaporated to dryness under
reduced pressure to obtain Clopidogrel besylate, which on
characterization showed to be the amorphous form.

[0029]The above process for preparing amorphous Clopidogrel besylate is
carried out using methyl isobutyl ketone and the like or mixture of THF
and methyl isobutyl ketone as a solvent.

EXAMPLE 2

Preparation of Crystalline Clopidogrel Besylate

[0030]Clopidogrel base (10 g) was dissolved in decan-1-ol at 50-55°
C. To this, benzene sulfonic acid (5 g) was added at 50-55° C. and
the reaction mixture was stirred for about 20 hr. The solid was filtered
and washed with methyl tertiary butyl ether and dried in vacuum oven for
at least 20 hr., to give Clopidogrel besylate, which on characterization
was found to be crystalline form. M.P. 130-135° C.

EXAMPLE 3

Preparation of Crystalline Clopidogrel Besylate

[0031]Clopidogrel base (10 g) was dissolved in decan-1-ol at 50-55°
C. To this, benzene sulfonic acid (5 g) was added at 50-55° C. The
reaction mixture was seeded with crystalline Clopidogrel besylate and the
reaction mixture was stirred for about 10 hr. The solid was filtered and
washed with methyl tertiary butyl ether dried in vacuum oven for at least
20 hr. to give Clopidogrel besylate, which on characterization was found
to be crystalline form.

M.P. 130-135° C.

EXAMPLE 4

Preparation of Crystalline Clopidogrel Besylate

[0032]Clopidogrel base (60 g) was dissolved in isopropanol at
50-55° C. To it was added benzene sulfonic acid (30 g) dissolved
in isopropanol at 50-55° C. The reaction mixture was stirred for
20 hr. The solid was filtered and washed with isopropanol and dried in a
vacuum oven for at least 20 hr. to give Clopidogrel besylate, which on
characterization was found to be crystalline form, M.P. 130-135°
C.

EXAMPLE 5

Preparation of Crystalline Clopidogrel Besylate

[0033]Clopidogrel base (30 g) was dissolved in isopropanol at
50-55° C. To this mixture benzene sulphonic acid (15 g) was added
at 50-55° C. The reaction mixture was stirred for 20 hr. The solid
was filtered and washed with cold isopropanol and dried in a vacuum oven
for at least 20 hr. to give Clopidogrel besylate, which on
characterization was found to be crystalline form. M.P. 130-135°
C.

EXAMPLE 6

Preparation of Crystalline Clopidogrel Besylate

[0034]Clopidogrel base (10 g) was dissolved in decan-1-ol at 50-55°
C. To this, benzene sulfonic acid (5 g) dissolved in decan-1-ol was added
at 50-55° C. The reaction mixture was seeded with crystalline
Clopidogrel besylate and the reaction mixture was stirred for about 20
hr. The solid was filtered and washed with methyl tertiary butyl ether
and dried in vacuum oven for at least 20 hr. to give Clopidogrel
besylate, which on characterization was found to be crystalline form.
M.P. 130-135° C.

EXAMPLE 7

Preparation of Crystalline Clopidogrel Besylate

[0035]Clopidogrel base (100 g) was dissolved in decan-1-ol at
50-55° C. To this, benzenesulfonic acid (50 g) dissolved in
decan-1-ol was added at 50-55° C. The reaction mixture was seeded
with crystalline Clopidogrel besylate (1 g) and the reaction mixture was
stirred for about 10 hr. The solid was filtered and washed with methyl
tertiary butyl ether and dried in vacuum oven for at least 20 hr. to give
Clopidogrel besylate, which on characterization was found to be
crystalline form. M.P. 130-135° C.

EXAMPLE 8

Preparation of Crystalline Clopidogrel Besylate

[0036]Clopidogrel base (5 g) was dissolved in methyl tertiary butyl ether.
To this, benzene sulfonic acid (2.5 g) dissolved in methyl tertiary butyl
ether was added at 50-55° C. The reaction mixture was seeded with
crystalline Clopidogrel besylate (50 mg) and the reaction mixture was
stirred for at least 24 hr. The solid was filtered and washed with methyl
tertiary butyl ether and dried in vacuum oven for at least 20 hr. to give
Clopidogrel besylate, which on characterization was found to be
crystalline form. M.P. 130-135° C.

EXAMPLE 9

Preparation of Crystalline Clopidogrel Besylate

[0037]Clopidogrel base (100 g) was dissolved in isopropanol at
50-55° C. To this, benzene sulfonic acid (50 g) dissolved in
isopropanol was added at 50-55° C. The reaction mixture was seeded
with crystalline Clopidogrel besylate (1 g) and the reaction mixture was
stiffed for about 10 hr. The solid was filtered and washed with
isopropanol and dried in vacuum oven for at least 20 hr. to give
Clopidogrel besylate, which on characterization was found to be
crystalline form. M.P. 130-135° C.

EXAMPLE 10

Preparation of Crystalline Clopidogrel Besylate

[0038]Clopidogrel base (100 g) was dissolved in isopropanol at
50-55° C. To this, benzene sulfonic acid (50 g) was added at
50-55° C. The reaction mixture was seeded with crystalline
Clopidogrel besylate (1 g) and the reaction mixture was stirred for about
10 hr. The solid was filtered and washed with isopropanol and dried in
vacuum oven for about 20 hr. to give Clopidogrel besylate, which on
characterization was found to be crystalline form. M.P. 130-135°
C.

EXAMPLE 11

Preparation of Crystalline Clopidogrel Besylate

[0039]Clopidogrel base (30 g) was dissolved in hexan-1-ol at 50-55°
C. To this, benzene sulfonic acid (15 g) dissolved in hexan-1-ol was
added at 50-55° C. The reaction mixture was seeded with
crystalline Clopidogrel besylate (1 g) and the reaction mixture was
stirred for about 10 hr. The solid was filtered and washed with methyl
tertiary butyl ether and dried in vacuum oven for at least 20 hr. to give
Clopidogrel besylate, which on characterization was found to be
crystalline form. M.P. 130-135° C.

[0040]The besylate salts of Clopidogrel prepared according to the
processes of the present invention can be administered to a person in
need of it either without further formulation, or formulated into
suitable formulations and dosage forms as are well known.

[0041]Some of the advantages of the processes for preparation of different
forms of Clopidogrel besylate according to the present invention are:
[0042]scalable at plant level and so industrially useful [0043]easy to
operate [0044]good recovery of solvents [0045]gives high yield